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Contraction/relaxation responses of myometrial small arteries.

Dose-response constriction curves to AVP (0.1–10 nmol/liter; 2-min intervals) or the thromboxane-mimetic U46619 (0.1–1000 nmol/liter; 2-min intervals) were constructed followed by relaxation to BK (0.1–1000 nmol/liter; 2-min intervals).

Vessels were washed to baseline tension and then incubated for 1 h in the presence of 0, 10, or 100 nmol/liter of the PDE5 inhibitor sildenafil citrate or UK-343664. The protocol of constriction to AVP or U46619/relaxation to BK was repeated as outlined above in the maintained presence of the PDE5 inhibitor.

Data were first tested whether they fitted to a Gaussian (normal) distribution using the Kolmogorov-Smirnov test.

Data that passed the normality test were compared using parametric statistical tests (unpaired/paired t test; repeated-measures ANOVA) and are represented as mean ± sem . All other data were compared using nonparametric statistical tests (Mann-Whitney U test) and are presented as median-range.

The effect of PDE5 incubation on agonist-induced constriction of myometrial small arteries was compared by paired t test.

BK-induced relaxation of myometrial small arteries was compared using repeated-measures ANOVA.

Data for the number of patients are indicated by (N). Women whose pregnancies were complicated by FGR delivered significantly earlier in gestation than the NP group ( P TABLE 1.

NP 27 30 (19–40) 2 (1–5) 1 (0–4) 123 (110–150) 75 (60–85) 38.9 (37.4–41.5) 3300 (2690–4110) 46 (7–88) FGR 12 28.5 (22–37) 3.5 (1–5) 1 (0–4) 120 (115–140) 81 (70–90) 37.9 (29.8–39.0) a 2460 (745–2860) b 3 (0–5) b.

NP 27 30 (19–40) 2 (1–5) 1 (0–4) 123 (110–150) 75 (60–85) 38.9 (37.4–41.5) 3300 (2690–4110) 46 (7–88) FGR 12 28.5 (22–37) 3.5 (1–5) 1 (0–4) 120 (115–140) 81 (70–90) 37.9 (29.8–39.0) a 2460 (745–2860) b 3 (0–5) b.

Demographic and clinical details are given for NP women and women whose pregnancies were complicated by FGR.

All data are median with range in parentheses for maternal age at delivery, gravidity, parity, maximum attained blood pressure (BP), gestation at delivery, birthweight, and IBR. Groups were compared statistically using the Mann-Whitney U test. NP 27 30 (19–40) 2 (1–5) 1 (0–4) 123 (110–150) 75 (60–85) 38.9 (37.4–41.5) 3300 (2690–4110) 46 (7–88) FGR 12 28.5 (22–37) 3.5 (1–5) 1 (0–4) 120 (115–140) 81 (70–90) 37.9 (29.8–39.0) a 2460 (745–2860) b 3 (0–5) b.

NP 27 30 (19–40) 2 (1–5) 1 (0–4) 123 (110–150) 75 (60–85) 38.9 (37.4–41.5) 3300 (2690–4110) 46 (7–88) FGR 12 28.5 (22–37) 3.5 (1–5) 1 (0–4) 120 (115–140) 81 (70–90) 37.9 (29.8–39.0) a 2460 (745–2860) b 3 (0–5) b. Demographic and clinical details are given for NP women and women whose pregnancies were complicated by FGR. All data are median with range in parentheses for maternal age at delivery, gravidity, parity, maximum attained blood pressure (BP), gestation at delivery, birthweight, and IBR. Groups were compared statistically using the Mann-Whitney U test.

Small arteries from women whose pregnancies were complicated by FGR showed significantly increased vasoconstriction compared with that seen in small arteries taken from NP women ( P 0.05, t test).

Addition of AVP to myometrial small arteries from women with FGR evoked maximal constriction of 21.5 ± 0.4 kPa (n = 24 arteries from seven patients) compared with 16.7 ± 0.4 kPa (n = 22 arteries from seven patients) in NP women ( P = 0.06, t test).

However, the sensitivity of myometrial small arteries from women whose pregnancies were complicated by FGR to AVP-induced vasoconstriction was not significantly altered compared with vessels from NP women (EC 50 , 0.47 ± 0.15 nmol/liter in FGR vs .

These data suggest modified vasoconstriction of myometrial small arteries from women whose pregnancies are complicated by FGR.

Effect of U46619 and AVP on myometrial small arteries from NP women and women whose pregnancies are complicated by FGR. Data are expressed as active effective pressure production in kPa.

All data are mean ± sem ; the x axis shows concentration of agonist ? 10 ?x .

?, NP (n = 13, top ; n = 14, bottom ); ?, FGR pregnancy (n = 10, top ; n = 6, bottom ).

Effect of U46619 and AVP on myometrial small arteries from NP women and women whose pregnancies are complicated by FGR. Data are expressed as active effective pressure production in kPa. All data are mean ± sem ; the x axis shows concentration of agonist ? 10 ?x .

?, NP (n = 13, top ; n = 14, bottom ); ?, FGR pregnancy (n = 10, top ; n = 6, bottom ). The effect of PDE5 inhibition on agonist-induced vasoconstriction is shown in Table 2. In NP, myometrial small arteries incubated with 100 nmol/liter sildenafil showed decreased constriction to AVP ( P = 0.002, paired t test). A similar trend was seen in vessels constricted with U46619, although this did not achieve statistical significance ( P = 0.14, paired t test).

In women with pregnancies complicated by FGR, myometrial small arteries incubated with 100 nmol/liter sildenafil showed decreased constriction with either AVP or U46619 ( P = 0.002 and P = 0.04, respectively, paired t test).

Additionally, 10 nmol/liter sildenafil showed decreased constriction with AVP-constricted small arteries ( P TABLE 2. Effect of incubation with sildenafil citrate on agonist-induced constriction of myometrial small arteries.

U46619 0 10.6 ± 1.0 (7) 10.7 ± 0.9 0.97 23.6 ± 1.3 (10) 22.2 ± 1.2 0.43 10 14.9 ± 1.1 (7) 12.9 ± 1.3 0.06 17.3 ± 0.8 (7) 15.7 ± 0.8 0.16 100 15.5 ± 0.6 (13) 14.5 ± 0.7 0.14 19.4 ± 0.7 (13) 17.2 ± 0.7 0.002 AVP 0 17.8 ± 1.0 (7) 16.0 ± 1.2 0.24 22.7 ± 1.0 (7) 23.2 ± 1.0 0.33 10 14.0 ± 0.9 (7) 12.3 ± 1.1 0.22 16.5 ± 0.9 (7) 14.9 ± 1.0 0.04 100 16.7 ± 1.2 (8) 14.0 ± 1.1 0.002 24.1 ± 1.0 (10) 20.8 ± 1.8 0.05.

U46619 0 10.6 ± 1.0 (7) 10.7 ± 0.9 0.97 23.6 ± 1.3 (10) 22.2 ± 1.2 0.43 10 14.9 ± 1.1 (7) 12.9 ± 1.3 0.06 17.3 ± 0.8 (7) 15.7 ± 0.8 0.16 100 15.5 ± 0.6 (13) 14.5 ± 0.7 0.14 19.4 ± 0.7 (13) 17.2 ± 0.7 0.002 AVP 0 17.8 ± 1.0 (7) 16.0 ± 1.2 0.24 22.7 ± 1.0 (7) 23.2 ± 1.0 0.33 10 14.0 ± 0.9 (7) 12.3 ± 1.1 0.22 16.5 ± 0.9 (7) 14.9 ± 1.0 0.04 100 16.7 ± 1.2 (8) 14.0 ± 1.1 0.002 24.1 ± 1.0 (10) 20.8 ± 1.8 0.05.

Data are expressed as active effective pressure production (kPa). Data at each concentration of PDE5 inhibitor were compared before and after PDE5 inhibitor using the paired Student’s t test.

Effect of incubation with sildenafil citrate on agonist-induced constriction of myometrial small arteries.

U46619 0 10.6 ± 1.0 (7) 10.7 ± 0.9 0.97 23.6 ± 1.3 (10) 22.2 ± 1.2 0.43 10 14.9 ± 1.1 (7) 12.9 ± 1.3 0.06 17.3 ± 0.8 (7) 15.7 ± 0.8 0.16 100 15.5 ± 0.6 (13) 14.5 ± 0.7 0.14 19.4 ± 0.7 (13) 17.2 ± 0.7 0.002 AVP 0 17.8 ± 1.0 (7) 16.0 ± 1.2 0.24 22.7 ± 1.0 (7) 23.2 ± 1.0 0.33 10 14.0 ± 0.9 (7) 12.3 ± 1.1 0.22 16.5 ± 0.9 (7) 14.9 ± 1.0 0.04 100 16.7 ± 1.2 (8) 14.0 ± 1.1 0.002 24.1 ± 1.0 (10) 20.8 ± 1.8 0.05.

U46619 0 10.6 ± 1.0 (7) 10.7 ± 0.9 0.97 23.6 ± 1.3 (10) 22.2 ± 1.2 0.43 10 14.9 ± 1.1 (7) 12.9 ± 1.3 0.06 17.3 ± 0.8 (7) 15.7 ± 0.8 0.16 100 15.5 ± 0.6 (13) 14.5 ± 0.7 0.14 19.4 ± 0.7 (13) 17.2 ± 0.7 0.002 AVP 0 17.8 ± 1.0 (7) 16.0 ± 1.2 0.24 22.7 ± 1.0 (7) 23.2 ± 1.0 0.33 10 14.0 ± 0.9 (7) 12.3 ± 1.1 0.22 16.5 ± 0.9 (7) 14.9 ± 1.0 0.04 100 16.7 ± 1.2 (8) 14.0 ± 1.1 0.002 24.1 ± 1.0 (10) 20.8 ± 1.8 0.05.

Data are expressed as active effective pressure production (kPa). Data at each concentration of PDE5 inhibitor were compared before and after PDE5 inhibitor using the paired Student’s t test.

Wire myography: relaxation responses of small arteries from myometrium. Alteration of endothelial function in pregnancies complicated by FGR.

U46619-constricted myometrial small arteries from NP women exhibited dose-dependent relaxation to increasing concentrations of BK ( Fig. This relaxation was significantly attenuated in arteries from women whose pregnancies were complicated by FGR (residual constriction, 43 ± 8% in FGR vs . 30 ± 5% in NP; IC 50 , 84 ± 15 nmol/liter in FGR vs .

14 ± 9 nmol/liter in NP; P = 0.001, repeated-measures ANOVA).

A similar relationship was seen with arteries constricted with AVP (residual constriction, 45 ± 12% in FGR vs .

80 ± 3% in NP; IC 50 , 21 ± 12 nmol/liter in FGR vs .

15 ± 7 nmol/liter in NP; P = 0.0009, repeated-measures ANOVA; Fig.

Endothelium-dependent relaxation of U46619-constricted myometrial small arteries. Data are expressed as percent maximal response to U46619. All data are mean ± sem ; x axis shows concentration of BK ? 10 ?x . Top , Arteries from NP (?; n = 14) and arteries from FGR pregnancy (?; n = 16 vessels from 12 patients); bottom , arteries from FGR pregnancy, BK-only control (•; n = 10), and arteries from FGR pregnancy, BK with 100 nmol/liter sildenafil citrate (0; n = 10). Data were compared before and after sildenafil by repeated-measures ANOVA. Endothelium-dependent relaxation of U46619-constricted myometrial small arteries. Data are expressed as percent maximal response to U46619. All data are mean ± sem ; x axis shows concentration of BK ? 10 ?x .

Top , Arteries from NP (?; n = 14) and arteries from FGR pregnancy (?; n = 16 vessels from 12 patients); bottom , arteries from FGR pregnancy, BK-only control (•; n = 10), and arteries from

FGR

Data were compared before and after sildenafil by repeated-measures ANOVA.

Endothelium-dependent relaxation of AVP-constricted myometrial small arteries. Data are expressed as percent maximal response to AVP.

All data are mean ± sem ; x axis shows concentration of BK ? 10 ?x .

Top , Arteries from NP (?; n = 14) and arteries from FGR pregnancy (?; n = 8); bottom , arteries from FGR pregnancy, BK-only control (•; n = 6), and arteries from FGR pregnancy, BK with 100 nmol/liter sildenafil citrate (0; n = 6). Data were compared before and after sildenafil by repeated-measures ANOVA. Endothelium-dependent relaxation of AVP-constricted myometrial small arteries.

Data are expressed as percent maximal response to AVP. All

data

In U46619-constricted arteries from women whose pregnancies were complicated by FGR, preincubation with 100 nmol/liter of the related PDE5 inhibitor UK-343664, also significantly enhanced relaxation [IC 50 , 10 ± 7 nmol/liter (100 nmol/liter) vs . Endothelium-dependent relaxation of U46619-constricted myometrial small arteries. Data are expressed as percent maximal response to U46619.

All data are mean ± sem ; x axis is concentration of BK ? 10 ?x . Arteries are from FGR pregnancy, BK-only control (?; n = 6), and from FGR pregnancy, BK with 100 nmol/liter UK-343664 (?; n = 6).

Data were compared before and after UK-343664 by repeated-measures ANOVA. Endothelium-dependent relaxation of U46619-constricted myometrial small arteries.

Data are expressed as percent maximal response to U46619. All data are mean ± sem ; x axis is concentration of BK ? 10 ?x . Arteries are from FGR pregnancy, BK-only control (?; n = 6), and from FGR pregnancy, BK with 100 nmol/liter UK-343664 (?; n = 6).

Data were compared before and after UK-343664 by repeated-measures ANOVA. PDE5 inhibition thus significantly enhanced endothelium-dependent vasorelaxation. We have previously demonstrated that, in contrast to NP, myometrial small arteries from women with preeclampsia show attenuated BK-induced endothelium-dependent relaxation ( 26, 27) and that relaxation was entirely mediated by NO ( 28). In this study, we have demonstrated for the first time that, as in preeclampsia ( 26– 28), there is aberrant myometrial small artery function flibanserin buy online in pregnancies complicated by FGR. Myometrial small arteries from pregnancies complicated by FGR show increased vasoconstriction and reduced endothelium-dependent relaxation compared with that seen in NP. The decreased uteroplacental flow, suggested by abnormal uterine artery Doppler in a significant number of women whose pregnancies are complicated by FGR ( 15) may be a direct result of this inappropriately increased vasoconstriction/reduced endothelium-dependent relaxation. Here, we hypothesized that inhibition of PDE using the PDE5-specific inhibitor sildenafil citrate would enhance NO-mediated relaxation in small myometrial arteries isolated from women with pregnancies complicated by fetal growth restriction.

The rationale behind this hypothesis stems from the similarities between the pathophysiologies associated with preeclampsia and viagra 25 mg tablet buy online FGR: a poorly modified uteroplacental vasculature ( 35) leading to a relative placental hypoperfusion and possible endothelial cell dysfunction ( 18, 19, 22– 24).

We have demonstrated that the PDE5 inhibitor sildenafil citrate limits the effects of vasoconstrictors in both NP and FGR.

A similar phenomenon has been suggested in the peripheral vasculature where sildenafil displays the characteristics of a mild NO donor ( 36); however, the major effects of sildenafil have been clearly demonstrated to be primarily a result of increases in cytosolic GMP ( 36– 38). We have also demonstrated that whereas sildenafil citrate does not significantly modify BK-induced endothelium-dependent relaxation in myometrial small arteries in NP women, there is a striking improvement in relaxation of small arteries from FGR pregnancies.

Incubation with sildenafil citrate effectively enhanced endothelium-dependent relaxation to levels seen in NP vessels.

Similar data were seen with UK-343664, a related PDE5-specific inhibitor.